期刊
JOURNAL OF CELL BIOLOGY
卷 217, 期 2, 页码 635-647出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201606095
关键词
-
类别
资金
- Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center Health System
- Richard King Mellon Foundation Institute for Pediatric Research
- Transatlantic Network of Excellence
- Fondation Leducq [15CVD03, RA15CVD04]
- National Institutes of Health [R-01AG035114, R56AG044519, AG021904]
- CHP Foundation
- Proteostasis of Aging [AG038072]
Chaperone-mediated autophagy (CMA) serves as quality control during stress conditions through selective degradation of cytosolic proteins in lysosomes. Humanin (HN) is a mitochondria-associated peptide that offers cytoprotective, cardioprotective, and neuroprotective effects in vivo and in vitro. In this study, we demonstrate that HN directly activates CMA by increasing substrate binding and translocation into lysosomes. The potent HN analogue HNG protects from stressor-induced cell death in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. The protective effects are lost in CMA-deficient cells, suggesting that they are mediated through the activation of CMA. We identified that a fraction of endogenous HN is present at the cytosolic side of the lysosomal membrane, where it interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. Inhibition of HSP90 blocks the effect of HNG on substrate translocation and abolishes the cytoprotective effects. Our study provides a novel mechanism by which HN exerts its cardioprotective and neuroprotective effects.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据